THEKNE-02967; No of Pages 6

The Knee xxx (xxxx) xxx

Contents lists available at ScienceDirect

The Knee

Relationship between serum resistin, body fat and

inflammatory markers in females with clinical knee
osteoarthritis
Eman M. Alissa a,b,⁎, Layla S. Alzughaibi a, Zuhair M. Marzouki a
a
Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
b
Elemental Spectroscopy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Adipokines have gained much interest in osteoarthritis (OA) pathogenesis studies
Received 22 May 2019
over the past years in that they play crucial roles in bone and cartilage homeostasis. Obesity
Received in revised form 21 November 2019
is known to be one of the well-recognized and modifiable causes of OA burden. Key mediators
Accepted 17 December 2019
Available online xxxx in this metabolic link between obesity and OA could be resistin, among other cytokines se-
creted by the adipose tissue. We aimed to evaluate the association of serum resistin with obe-
sity, and inflammation in female patients with knee OA.
Keywords:
Resistin Methods: One hundred female participants, aged above 40 years, with symptomatic primary
hs-CRP knee OA were matched for age with 100 apparently healthy females in a case–control study
BMI design. All study participants were subjected to clinical examination, laboratory investigations
Waist circumference and radiological examination.
WOMAC
Results: Patients with primary knee OA had elevated levels of serum resistin compared with
healthy controls. We demonstrated that elevated serum resistin positively correlated with ad-
iposity measures, inflammatory markers and WOMAC index. High sensitivity C reactive protein
was found to be an independent predictor of serum resistin levels after adjustment for con-
founder factors.
Conclusions: These results indicate that resistin may play an important role in the progression
of knee OA and may serve as a novel and reliable biomarker for reflecting disease severity, with
the potential to contribute to the fundamental processes underlying the pathogenesis of knee
OA.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction

Osteoarthritis (OA) is one of the most common degenerative joint diseases in the aging population affecting any articular, with
the knee joints most commonly involved [1]. OA is characterized by the progressive deterioration of the articular cartilage and
structural changes to the entire synovial joint, including the synovium, meniscus of knee, adipose tissue, periarticular ligaments
and subchondral bone [2]. The etiology of OA is multifactorial, classically related to mechanical factors, trauma, or overload [3].
A sex discrepancy has been observed in the prevalence and incidence of OA, with females at greater risk [4]. For knee OA, strong
evidence indicates a variety of moderate to strong risk factors, including female sex, obesity, and previous knee injury [5]. Genetic,

⁎ Corresponding author at: Faculty of Medicine, King Abdulaziz University, PO Box 12713, Jeddah 21483, Kingdom of Saudi Arabia.
E-mail address: ealissa@kau.edu.sa. (E.M. Alissa).

https://doi.org/10.1016/j.knee.2019.12.009
0968-0160/© 2020 Elsevier B.V. All rights reserved.

Please cite this article as: E.M. Alissa, L.S. Alzughaibi and Z.M. Marzouki,
Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009
2 E.M. Alissa et al. / The Knee xxx (xxxx) xxx

anthropometric, metabolic, and local inflammatory factors have been implicated in the pathophysiology of OA [6]. Different epi-
demiologic studies have shown a high prevalence of cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes, obe-
sity, and metabolic syndrome in patients with knee OA [7]. Recently, biochemical markers represent a possible non-invasive
method to assess the risk for the progression of the disease, detect early changes of the disease and evaluate the response to
such potential disease-modifying OA drugs [8,9].
Adipokines have gained much interest in OA pathogenesis studies over the past years in that they play crucial roles in bone
and cartilage homeostasis [10,11]. Of those, resistin has been investigated with its occurrence and potential involvement in the
pathophysiology of OA. In human studies, it has been shown that synovial fluid and serum resistin levels increase in patients
after knee injury [12] as well as in OA patients, indicating resistin's involvement in inflammatory changes of OA [13,14]. In addi-
tion to its pro- or anti-inflammatory functions, resistin in synovial fluid was found to be positively associated with obesity [15].
Thus, indicating that adipokines might represent other crucial mediators that links inflammation with obesity in knee OA patients.
All these data indicate that resistin may play crucial roles in OA progression.
Obesity has received much scientific interest as one of the well-recognized and modifiable causes of this rising OA burden [16].
However, the relationship between obesity and OA may not simply be due to weight-related increased load on the joint, because
body mass index (BMI) has been associated with the development of OA in non-weight-bearing joints such as the hands [17].
Moreover, it has been shown that risk of primary knee and hip joint replacement for OA relates to both adipose mass and central
adiposity [18]. This is suggestive of a potential link between dysfunctional metabolism and joint damage [19]. Key mediators in
this metabolic link between obesity and OA could be resistin, among other cytokines secreted by the adipose tissue [20].
The exact role of adipokines in knee OA is not well known, but they may play a significant role indirectly via their link to obe-
sity and directly on OA pathways in many patients. Only a limited number of small clinical studies on systemic adipokines in knee
OA have been performed. Moreover, previous studies of adipokines were performed in patients with advanced disease undergoing
prosthetic surgery and were not focused on severity or on the inflammatory profile of knee OA. To our knowledge, no clinical
study thus far has evaluated a possible relationship between resistin and knee OA in females. Thus, the present study was carried
out to evaluate the association of serum resistin with obesity, and inflammation in female patients with knee OA.

2. Methods

A case–control study was conducted among 100 female participants, aged above 40 years, with symptomatic primary knee OA.
They were consecutively recruited from the Orthopaedics Department, Faculty of Medicine, King Abdulaziz University Hospital
(KAUH), Jeddah, Saudi Arabia. One hundred age-matched control females were recruited from the same catchment area, and
they had no signs of OA-related symptoms and radiographic changes. All study participants were subjected to clinical examina-
tion, laboratory investigations and radiological examination. Written informed consent was obtained from each patient and the
study was approved by the Ethical Committee of KAUH. This study was supported by a grant number (KACST, 36-89) from the
KACST.
All patients met the American College of Rheumatology criteria for the diagnosis of OA [21]. Exclusion criteria included: sec-
ondary OA, such as those with a history of trauma, meniscal injury, inflammatory rheumatic or septic conditions, previous knee
surgery, auto-immune diseases, malignant disease, acute or chronic renal disease. In addition, subjects were excluded if they used
anti-inflammatory drugs, systemic glucocorticoid intake, intraarticular glucocorticoid or hyaluronic acid injection.
The symptomatic severity of OA was assessed by the Arabic translated and validated version of Western Ontario and McMaster
Universities (WOMAC) index [22]. The psychometric properties of the WOMAC score have been shown to be valid and reliable in
patients with primary knee OA [23,24].
Radiographic assessment was performed by a radiology specialist using the Kellgren–Lawrence (K-L) grading system (grades
0–4): grade 0, normal; grade 1, no joint space narrowing (JSN), suspicious osteophytes; grade 2, suspicious JSN, mild osteophytes;
grade 3, definite JSN, moderate osteophytes, and/or subchondral bone sclerosis; and grade 4, marked JSN, large osteophytes, and/
or severe subchondral bone sclerosis [25]. Radiographic OA was defined as a K-L grade ≥ 2.
Weight was measured in minimum clothing to the nearest 0.1 kg using a calibrated scale. Height was measured to the nearest
0.1 cm using a stadiometer. Waist measurement (WC) was taken at the narrowest diameter between xiphoid process and iliac
crest, whereas hip measurement (HC) was taken at the widest diameter over greater trochanters. BMI and waist-hip ratio
(WHR) were then calculated.
Venous blood samples were obtained from the study subjects after 12-h fasting. The specimens were then centrifuged (at
1000 g at 4 °C for 10 min) within 30 min of blood sampling. Serum was aliquoted and frozen at −80 °C until time of analysis.
Complete blood count and erythrocyte sedimentation rate (ESR) were performed for all samples. Quantitative determination of
high sensitivity C reactive protein (hs-CRP) concentration was carried out using the immunoturbidimetry method (Roche Diag-
nostics GmbH, Mannheim, Germany). Serum levels of resistin were measured by enzyme-linked immunosorbent assay (ELISA)
kits (Bio Vender, Brno, Czech Republic) according to the manufacturer's instructions.
Data are described as mean ± standard error of the mean, frequency (percentage) as appropriate. The distribution of variables
was analyzed with Kolmogorov–Smirnov test. Comparison for sequential values between the two groups was performed by un-
paired Student's t-test and Mann–Whitney test, for parametric and nonparametric data, respectively. For comparing categorical
data, a Chi-squared test was performed. Pearson's correlations or Spearman's analyses were used to analyze the correlations of
serum levels of resistin with all parameters. A stepwise multiple regression model was performed to determine the relationships
between serum resistin (as the dependent variable) with anthropometric and biochemical variables with P-values up to 0.1 (as

Please cite this article as: E.M. Alissa, L.S. Alzughaibi and Z.M. Marzouki,
Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009
 E.M. Alissa et al. / The Knee xxx (xxxx) xxx 3

independent variables). A P-value b .05 was considered statistically significant. All statistical calculations were carried out using
the Statistical Package for the Social Sciences (SPSS) program, version 21.0 (SPSS Inc., Chicago, IL, USA).

3. Results

Two hundred females with and without knee OA were matched for age. The disease duration ranged from 0 to five years. The
percentages of central obesity among the study population according to the cut offs of WHR and WC were 100% and 96%,
respectively.
Clinical characteristics are presented in Table 1. Knee OA patients showed significantly higher mean values of body height,
waist and hip circumferences and WHR than the control subjects (P b .05). More OA patients were overweight (46% vs. 36%)
in comparison with more controls being obese (49% vs. 33%) according to BMI classes. Compared with healthy controls, mean
serum levels of ESR and hs-CRP were significantly higher among knee OA patients (P b .0001 each).
Female patients with knee OA had significantly higher mean WOMAC scores than their age-matched control counterparts
(P b .0001). The predominant WOMAC grades were mild (12%) and moderate (83%), and only 5% of our knee OA patients
were classified as WOMAC grade severe.
Notably, Figure 1 demonstrates significantly higher mean serum levels of resistin among OA patients than the control group
(P b .0001). Also, median resistin levels showed a non-significant increase across the three BMI classes (Figure 2).
Table 2 displays associations between serum resistin and all investigated parameters. All anthropometric parameters achieved
statistical significance, with ESR, hs-CRP and WOMAC index showing the strongest associations.
Stepwise multiple regression analysis for serum resistin was conducted in a model that included all independent variables
with P-value up to 0.1 to demonstrate their contribution to resistin level. In this model, 5.2% of the variability in serum resistin
could be explained by only hs-CRP (β = −0.228, P = .004, 95% confidence interval: −3.432 to −0.651), after adjustment for
other confounding factors.

4. Discussion

The increased OA morbidity calls for urgency to make early diagnosis, prevention, and treatment. In recent years, biochemical
markers show promise in determination of the disease severity [26]. The presence of local joint inflammation and altered cartilage
and bone turnover in OA implicates a potential role for adipokines in OA progression.
The current study investigated the relationship between serum resistin with obesity and inflammation in female patients with
knee OA. We found that general obesity and central obesity were highly prevalent among the study population. Higher BMI was
previously linked with the risk of developing knee OA [27,28]. Moreover, obese women have an even higher risk for developing
knee osteoarthritis than their male counterparts [4]. Although the association between obesity and knee OA has classically been
attributed to biomechanical mechanisms, more recently humoral mechanisms have been implied [28].
We have demonstrated that serum resistin levels showed a non-significant ascending trend across BMI classes (Figure 2). Fur-
thermore, positive associations were observed between serum resistin and all anthropometric measures (Table 2). Resistin levels
have previously showed positive association with central and visceral obesity, but not BMI [29]. The association between resistin

Table 1
Anthropometric and biochemical characteristics of the study population (n = 200).

Controls OA patients P
(n = 100) (n = 100)

Age (years) 50.3 ± 0.5 50.5 ± 0.5 NS

Body weight (kg) 76.9 ± 0.9 75.9 ± 1.0 NS
Body height (cm) 159.9 ± 0.7 163.4 ± 0.6 b0.0001
BMI (kg/m2) 30.2 ± 0.5 28.5 ± 0.4 b0.05
BMI classes
Normal (≤24.9 kg/m2) 15 (15) 21 (21)
Overweight (25–29.9 kg/m2) 36 (36) 46 (46) b0.05
Obese (≥30 kg/m2) 49 (49) 33 (33)
WC (cm) 105.5 ± 0.9 110.0 ± 0.9 b0.01
HC (cm) 62.9 ± 0.5 64.8 ± 0.5 b0.05
WHR 1.68 ± 0.0 1.71 ± 0.0 NS
WBC (×109/L) 8.01 ± 0.2 8.02 ± 0.2 NS
ESR (mm/h) 5.80 ± 0.4 30.5 ± 0.9 b0.0001
hs-CRP (mg/L) 0.55 ± 0.0 1.21 ± 0.1 b0.0001
hs-CRP classes
Low risk 96 (96) 51 (51)
Intermediate risk 4 (4) 49 (49) b0.0001
High risk 0 (0) 0 (0)

Data are presented as mean ± standard error of the mean and as frequency (percentage). Continuous variables were compared unpaired Student's t-test or Mann–
Whitney test for non-normally distributed data. Categorical variables are compared by χ2 test. BMI, body mass index; ESR, erythrocytes sedimentation rate; HC, hip
circumference; hs-CRP, high sensitivity-C reactive protein; NS, not significant; WC, waist circumference; WBC, white blood cells count; WHR, waist hip ratio;
WOMAC, Western Ontario and McMaster Universities.

Please cite this article as: E.M. Alissa, L.S. Alzughaibi and Z.M. Marzouki,
Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009
4 E.M. Alissa et al. / The Knee xxx (xxxx) xxx

p<0.0001

10
9
8

serum resistin (ng/ml)

7
6
5
4
3
2
1
0
control OA paents

Figure 1. Mean ± standard error of the mean of serum resistin levels in patients with osteoarthritis (OA) and age-matched controls (P b .0001).

and obesity is stronger in women than in men [30], although opposite results were reported in other studies [31]. These conflict-
ing findings point towards the idea that the pro-inflammatory or anti-inflammatory function of resistin is context related and dis-
ease specific.
Serum levels of resistin among knee OA patients were considerably higher compared with healthy controls (P b .0001). This
finding is in agreement with the suggestion of systemic and local involvement of resistin in inflammatory changes of OA [12].
Also, serum levels of resistin were positively and independently associated with cartilage defects and bone marrow lesions in pa-
tients with knee OA [32]. On the contrary, other investigators did not find any correlation between serum and synovial fluid con-
centration of resistin among patients with and without knee OA [20]. Plasma resistin concentrations were found to be positively
associated with the prevalence and incidence of radiographic knee OA, independently on BMI, but it was not associated with dis-
ease progression [33]. Similarly, it was reported that plasma levels of resistin were significantly associated with radiographic knee
OA [34] as well as with the grade of synovial tissue inflammation [20]. Indeed, resistin itself does not damage joints and cartilage,
with potential contribution to the fundamental processes underlying the pathogenesis of knee OA. Thus, resistin levels may be
valuable for early detection in OA patients.
Similar to our findings, resistin levels were found to be correlated with fat mass and CRP [35,36]. Adipose tissue mediates the
secretion of pro-inflammatory cytokines, such as interleukin-6, which in turn triggers the hepatic synthesis of CRP [37]. It is be-
lieved that in humans, resistin plays a more important role in inflammatory processes than in insulin resistance, as serum resistin
levels correlate better with subclinical inflammation than with insulin resistance [38].

Figure 2. Median serum resistin levels among the study population (n = 200) categorized by body mass index (BMI) groups: normal weight if BMI ≤24.9 kg/m2,
overweight (OW) if BMI between 25.0 and 29.9 kg/m2, and obesity if BMI ≥30.0 kg/m2 (P N .05).

Please cite this article as: E.M. Alissa, L.S. Alzughaibi and Z.M. Marzouki,
Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009
 E.M. Alissa et al. / The Knee xxx (xxxx) xxx 5

Table 2
Univariate analysis of serum resistin with anthropometric and biochemical characteristics of the study population (n = 200) by Pearson or Spearman correlation anal-
ysis, where appropriate.

r P

Body height 0.262 b0.0001

BMI 0.175 b0.05
WC 0.255 b0.0001
HC 0.139 b0.05
WHR 0.154 b0.05
ESR 0.869 b0.0001
hs-CRP 0.498 b0.0001
WOMAC index 0.884 b0.0001

BMI, body mass index; ESR, erythrocytes sedimentation rate; HC, hip circumference; hs-CRP, high sensitivity-C reactive protein; WC, waist circumference; WHR,
waist hip ratio; WOMAC, Western Ontario and McMaster Universities.

We demonstrated that ESR, hs-CRP and WOMAC index had strong associations with serum levels of resistin (Table 2). Our re-
sults are consistent with other reports describing a correlation between serum resistin concentration, ESR and CRP in patients
with OA [39]. The role of resistin in OA could be explained by its action as an inducer of pro-inflammatory cytokines signaling
pathway in diverse inflammatory conditions [40]. Other authors have found that resistin level in synovial fluid but not in
serum is significantly associated with Kellgren–Lawrence grades and WOMAC pain in knee OA patients [41]. Arguably, it is plau-
sible to suggest that systematic inflammation leads to increased resistin production and circulatory levels in humans. The in-
creased level of resistin in humans with obesity is likely an indirect result of elevated levels of inflammatory cytokines
characteristics due to increased adiposity.
Conventional laboratory markers such as hs-CRP have been shown to be elevated in early phases of OA [1] suggesting the
presence of low-grade inflammation, which supports a pathophysiological role of inflammation at early stages of the disease pro-
cess. In our study, the correlation with serum hs-CRP was further evaluated by multiple regression analysis and it was still signif-
icant after adjusting for other confounding factors, including anthropometric measures. This might be because BMI is highly
correlated with hs-CRP, when both obesity and hs-CRP are evaluated simultaneously, hs-CRP does not remain significantly asso-
ciated with incident knee OA [42].
There are several limitations that should be taken into account. First, the observational study design does not imply causation;
therefore, our findings should be validated in long-term prospective studies. Second, we only examined resistin, which is one of
many adipokines, such as leptins and adiponectin that are involved in the progression of OA. Their correlations with OA deserve
further intensive study. Lastly, the levels of resistin were measured in serum, as opposed to synovial fluid, which did not allow us
to detect local effects. Other diagnostic imaging modalities such as ultrasonography and magnetic resonance imaging might be
more sensitive and accurate to detect minor or minimal radiographic changes as well as soft tissue structural damage [1].
In conclusion, patients with primary knee OA, as evaluated by radiography, had elevated levels of serum resistin compared
with healthy controls. We demonstrated that elevated serum resistin positively correlated with adiposity measures, inflammatory
markers and WOMAC index. hs-CRP was found to be an independent predictor of serum resistin levels after adjustment for con-
founder factors. These results indicate that resistin may play an important role in the development of knee OA and therefore may
serve as a novel reliable biomarker for reflecting disease severity. More studies are required to confirm this and to determine suit-
able threshold values for diagnostic purposes.

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgments

This study was supported by a grant number KACST 36-89 from the KACST. The funding source had no role in publication. We
would like to thank all the individuals who took part in the study. The contributions of the authors are as follows: E.A. and Z.M.
designed the research; L.Z. conducted subject recruitments and data collection; E.A. analyzed data and wrote the paper; E.A. had
primary responsibility for the final content. All authors read and approved the final manuscript.

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Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009
6 E.M. Alissa et al. / The Knee xxx (xxxx) xxx

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Please cite this article as: E.M. Alissa, L.S. Alzughaibi and Z.M. Marzouki,
Relationship between serum resistin, body fat and inflammatory markers in females with clinical kne..., The Knee, https://doi.org/
10.1016/j.knee.2019.12.009